The extracellular calcium-sensing receptor (CaSR) most likely plays a critical role in modulating the kidney's response to calcium and its processing of other electrolytes, but its exact function and mechanisms of action in the kidney have yet to be elucidated. To determine the role of CaSR in the kidney, a transgenic mouse model over expressing the CaSR in the distal tubules of the kidney will be developed and the effect of over expression and subsequent increased activation of CaSR on whole animal physiology and cellular physiology examined. The effect of activation of CaSR in the distal tubules of the kidney on renal calcium reabsorption, uniary concentrating ability, apical potassium channel activity, and cyclic-AMP generation in response to vasopressin will be determined. The potential clinical significance of this work is far-reaching. Determine the role of CaSR in the kidney will certainly shed light on the rare genetic disorders resulting from mutations in CaSR, but it should also improve understanding of primary processes in nephrolithiasis, osteoporosis, parathyroid disorders, and possibly even essential hypertension.